Central Nervous System Pathways Research Articles

Ciliary neurotrophic factor and leptin induce distinct patterns of immediate early gene expression in the brain.

Ciliary neurotrophic factor (CNTF) and leptin decrease food intake and body weight. Lipopolysaccharide (LPS) is a potent exogenous pyrogen and produces anorexia via cytokine production. CNTF-, leptin-, and LPS-induced cytokines all act on type I cytokine receptors. However, it is not known if these cytokines engage similar central nervous system (CNS) pathways to exert their effects. To assess mechanisms by which these cytokines act, we examined the patterns of immediate early gene expression (SOCS-3, c-fos, and tis-11) in the brain following intravenous administration. CNTF and LPS induced gene expression in circumventricular organs; ependymal cells of the ventricles, meninges, and choroid plexus; and the arcuate nucleus of the hypothalamus. CNTF administration also induced fever and cyclooxygenase-2 mRNA expression. In contrast, we found no evidence of leptin-induced inflammation. CNTF and leptin are being assessed as potential therapeutic anti-obesity agents, and both potently reduce food intake. Our findings support the hypothesis that CNTF and leptin engage distinct CNS sites and CNTF possesses inflammatory properties distinct from leptin.

Parallel processing in an identified neural circuit: the Aplysia californica gill-withdrawal response model system.

The response of the gill of Aplysia calfornica Cooper to weak to moderate tactile stimulation of the siphon, the gill-withdrawal response or GWR, has been an important model system for work aimed at understanding the relationship between neural plasticity and simple forms of non-associative and associative learning. Interest in the GWR has been based largely on the hypothesis that the response could be explained adequately by parallel monosynaptic reflex arcs between six parietovisceral ganglion (PVG) gill motor neurons (GMNs) and a cluster of sensory neurons termed the LE cluster. This hypothesis, the Kupfermann-Kandel model, made clear, falsifiable predictions that have stimulated experimental work for many years. Here, we review tests of three predictions of the Kupfermann-Kandel model: (1) that the GWR is a simple, reflexive behaviour graded with stimulus intensity; (2) that central nervous system (CNS) pathways are necessary and sufficient for the GWR; and (3) that activity in six identified GMNs is sufficient to account for the GWR. The available data suggest that (1) a variety of action patterns occur in the context of the GWR; (2) the PVG is not necessary and the diffuse peripheral nervous system (PNS) is sufficient to mediate these action patterns; and (3) the role of any individual GMN in the behaviour varies. Both the control of gill-withdrawal responses, and plasticity in these responses, are broadly distributed across both PNS and CNS pathways. The Kupfermann-Kandel model is inconsistent with the available data and therefore stands rejected. There is, no known causal connection or correlation between the observed plasticity at the identified synapses in this system and behavioural changes during non-associative and associative learning paradigms. Critical examination of these well-studied central pathways suggests that they represent a 'wetware' neural network, architecturally similar to the neural network models of the widely used 'Perceptron' and/or 'Back-propagation' type. Such models may offer a more biologically realistic representation of nervous system organisation than has been thought. In this model, the six parallel GMNs of the CNS correspond to a hidden layer within one module of the gill-control system. That is, the gill-control system appears to be organised as a distributed system with several parallel modules, some of which are neural networks in their own right. A new model is presented here which predicts that the six GMNs serve as components of a 'push-pull' gain control system, along with known but largely unidentified inhibitory motor neurons from the PVG. This 'push-pull' gain control system sets the responsiveness of the peripheral gill motor system. Neither causal nor correlational links between specific forms of neural plasticity and behavioural plasticity have been demonstrated in the GWR model system. However, the GWR model system does provide an opportunity to observe and describe directly the physiological and biochemical mechanisms of distributed representation and parallel processing in a largely identifiable 'wetware' neural network.

The emotional brain: neural correlates of cat sexual behavior and human male ejaculation

The organization of virtually all basic survival mechanisms in the central nervous system (CNS) is within the most central regions of the mesencephalon and the rostrally adjoining diencephalon; in particular, the mesencephalic periaqueductal gray (PAG) and hypothalamus. The PAG sends specific pathways to the caudal brainstem where neurons are located that, in turn, control nociception, blood pressure, heart rate, and micturition. Via projections to the nucleus retroambiguus (NRA) in the most caudal part of the medulla, the PAG controls the intra-abdominal pressure associated with vocalization, vomiting, and parturition. In cats, the PAG also controls sexual posture via NRA projections to motoneurons in the lumbosacral cord. These NRA-lumbosacral motoneuronal pathways are almost nine times stronger in the estrous vs. non-estrous female cat. While neuronal activity in specific CNS pathways is now known to control sexual behavior in the cat, how is it organized in the human? PET-scan results on human ejaculation have revealed that the meso-diencephalic transition zone is particularly and strongly activated. This region includes the so-called ventral tegmental area that is also known as a "reward area." For example, it is also activated during a heroin rush. Other strongly activated structures during sexual activity include the cerebellum and lateral part of the corpus striatum. At the level of the cerebral cortex, areas in the prefrontal and parietal cortex are also activated, but exclusively on the right side. Further study of these structures should certainly lead to better insight into human sexual behavior and provide the possibility to improve sexual activity in those who suffer from problems in this area.

A gene expression atlas of the central nervous system based on bacterial artificial chromosomes.

The mammalian central nervous system (CNS) contains a remarkable array of neural cells, each with a complex pattern of connections that together generate perceptions and higher brain functions. Here we describe a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes and pathways. We illustrate the use of this atlas to derive novel insights into gene function in neural cells, and into principal steps of CNS development. The atlas, library of BAC vectors and BAC transgenic mice generated in this screen provide a rich resource that allows a broad array of investigations not previously available to the neuroscience community.

MK-801 and 7-Ni attenuate the activation of brain NF-κB induced by LPS

The activation of nuclear factor-κB (NF-κB) leads to an increase in the expression of genes involved in important events in the central nervous system (CNS), such as development, plasticity and inflammation. It has been shown that inflammatory stimulus in the brain increases excitatory glutamatergic transmission, especially at N-methyl- d-aspartate (NMDA) receptor. These receptors have an important role in glutamate neurotoxicity and are in general coupled with the generation of nitric oxide (NO) through the activation of neuronal nitric oxide synthase (NOS). We have investigated the involvement of NMDA–NO pathway in LPS induction of NF-κB in CNS. Our results demonstrate that systemic LPS activates NF-κB in several regions of the CNS, which was partially reduced by the NMDA receptor antagonist dizolcipine (MK-801) and by the selective brain NOS inhibitor 7-Nitroindazol (7-Ni). 7-Ni effects were not synergic to MK-801 effects, suggesting that these compounds act through the same pathway. Dexamethasone caused a stronger reduction in LPS induction of NF-κB in CNS, demonstrating that MK-801 and 7-Ni act on a pathway that is responsible only by a fraction of the overall NF-κB activation. These results suggest that a considerable part of NF-κB activation by LPS is linked to the NMDA/NO pathway in CNS.

Effect of central administration of interleukin-1 receptor antagonist on protein synthesis in skeletal muscle, kidney, and liver during sepsis

Inflammatory cytokines may mediate the host response to infection via central nervous system (CNS), endocrine, and/or paracrine pathways. The purpose of the present study was to determine whether intracerebroventricular (ICV) infusion of interleukin-1 receptor antagonist (IL-1ra) influences the effects of sepsis on protein metabolism in peripheral organs (skeletal muscle, kidney, and liver). A constant ICV infusion of IL-1ra (100 μg/h) or saline was begun immediately before the induction of sepsis or sterile inflammation and continued for 5 days. ICV infusion of IL-1ra did not alter protein metabolism in animals with a sterile abscess. Sepsis reduced muscle weight, protein content, and rates of protein synthesis in gastrocnemius. ICV infusion of IL-1ra attenuated the sepsis-induced loss of muscle mass and protein and the inhibition of protein synthesis in gastrocnemius by augmenting the translational efficiency. Similar results were observed in kidney, with respect to kidney weight, total protein, rates of protein synthesis, and translational efficiency. However, central infusion of IL-1ra did result in a small (12%) increase in the renal RNA content in either sterile or septic abscess rats. In liver, ICV infusion of IL-1ra prevented the sepsis-induced inhibition of protein synthesis and reduction in translational efficiency. These results suggest that central administration IL-1ra can modulate protein metabolism in peripheral organs during sepsis by preventing the sepsis-induced defects in the translational efficiency.

Hydrochloric Acid Induced Changes in Macrophage Migration Inhibitory Factor in the Bladder, Peripheral and Central Nervous System of the Rat.

We established the presence of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) in the bladder and in nervous system structures innervating the bladder, and evaluated changes in MIF and cyclooxygenase-2 (COX-2) protein levels and expression following chemical cystitis. Male Sprague-Dawley rats were anesthetized and a catheter was introduced into the bladder dome. Cystitis was induced by infusing 0.4 N HCl into the bladder. Control rats received a similar volume of saline. Two hours later the bladder, major pelvic ganglia (MPG), L6/S1 dorsal root ganglia (DRG) and L6/S1 spinal cord were removed and assayed for MIF and COX-2 protein, and mRNA using Western blot and quantitative reverse transcriptase-polymerase chain reaction techniques. Immunohistochemistry showed MIF located mainly in the urothelium of saline treated rats. Instillation of HCl into the bladder resulted in marked epithelial denudation, moderate edema and vasodilatation in the submucosa. MIF protein levels decreased but MIF mRNA expression remained unchanged in bladders treated with HCl compared with controls. However, MIF protein and mRNA levels increased in the MPG, L6/S1 DRG and L6/S1 spinal cord of HCl treated animals. COX-2 protein was not detected in the bladder, DRG or MPG of saline-treated rats. However, a small amount was present in the L6/S1 cord. On the other hand, HCl treated rats showed marked increases in COX-2 protein levels in all tissues examined. Similarly although cox-2 mRNA was constitutively expressed in all tissues examined, expression increased following HCl treatment. Chemical cystitis induced by intravesical HCl in rats increases the protein levels and mRNA expression of MIF and COX-2 in central and peripheral nervous system tissues that are involved in innervating the bladder. This finding suggests that MIF may be involved in bladder inflammation and may have a role in the peripheral and central nervous system pathways that regulate bladder reflexes in response to bladder inflammation.

The COOH-terminal domain of agrin signals via a synaptic receptor in central nervous system neurons.

Agrin is a motor neuron–derived factor that directs formation of the postsynaptic apparatus of the neuromuscular junction. Agrin is also expressed in the brain, raising the possibility that it might serve a related function at neuron–neuron synapses. Previously, we identified an agrin signaling pathway in central nervous system (CNS) neurons, establishing the existence of a neural receptor that mediates responses to agrin. As a step toward identifying this agrin receptor, we have characterized the minimal domains in agrin that bind and activate it. Structures required for agrin signaling in CNS neurons are contained within a 20-kD COOH-terminal fragment of the protein. Agrin signaling is independent of alternative splicing at the z site, but requires sequences that flank it because their deletion results in a 15-kD fragment that acts as an agrin antagonist. Thus, distinct regions within agrin are responsible for receptor binding and activation. Using the minimal agrin fragments as affinity probes, we also studied the expression of the agrin receptor on CNS neurons. Our results show that both agrin and its receptor are concentrated at neuron–neuron synapses. These data support the hypothesis that agrin plays a role in formation and/or function of CNS synapses.

Pharmacological therapy of obesity: past, present, and future.

There is probably no medical condition for which a safe and effective form of pharmacotherapy is more highly desired than obesity. Neither is there a condition for which effective treatment would spare so much suffering for so many individuals. There is abundant evidence from epidemiological and interventional studies to suggest that morbidity from diabetes, cardiovascular disease, cerebrovascular disease, osteoarthritis, sleep apnea, and certain cancers could all be reduced in proportion to a reduction in body fat content. Past forms of pharmacotherapy for obesity have often been misguided, and currently available drugs are less effective than we would like them to be. However, our growing understanding of peripheral signals and central nervous system (CNS) pathways involved in the regulation of adiposity makes it very likely that effective new drugs will become available to treat obesity in the near future. This review will provide a brief history of obesity pharmacotherapy, discuss the status of currently available obesity drugs, and outline the major physiological pathways that will form the targets for future drug development. The past

Sympathetic over activity in the etiology of hypertension of obstructive sleep apnea.

Beginning with modest clinical observations in 1984, a picture has evolved suggesting that sympathetic nervous system over activity may be responsible in part for the elevated blood pressure seen in obstructive sleep apnea patients. Early studies of urinary and plasma catecholamines indirectly suggested sympathetic over activity carried to daytime, non-apneic conditions. Later intra-neuronal recordings of muscle sympathetic nerve activity directly demonstrated both acute and diumal (non-apneic) sympathetic over activity. Most importantly, diurnal sympathetic over activity has been shown to diminish with adequate treatment of apnea using nasal CPAP. Norepinephrine and angiotensin II are both released with increased peripheral sympathetic activity and are parallel vascular growth-promoting factors. Thus, one would expect alterations in vascular structure and function in a state of chronic sympathetic over activity. While changes in peripheral vascular structure have not been demonstrated in hypertension of sleep apnea, changes in peripheral vascular responsiveness have. There is reduced response to acetylcholine and isoproterenol vasodilation, and to norepinephrine and angiotensin vasoconstriction in humans with sleep apnea. Some of these vascular reactivity changes are shown to reversed with chronic nasal CPAP treatment. Finally, complimentary to the above evidence in humans, there is indirect evidence of sympathetic over activity as well as differences in vascular reactivity in intermittent hypoxia challenged rats. We have made significant strides in the past 15-20 years towards understanding systemic hypertension related to sleep apnea, especially the role of the sympathetic nervous system. Future research will need to look at exact mechanism of sympathetic nervous system over activity, particularly how central nervous system pathways may undergo facilitation, leading to daytime over activity. Furthermore, the mechanisms of sustained hypertension in sleep apnea patients is almost certainly of multiple etiologies. There is no marker for separating sleep apnea patients with hypertension derived solely from intermittent hypoxia from other secondary causes. Perhaps endothelial cell molecular markers could help to identify patients at risk for cardiovascular change associated with snoring and apnea, as well to guide treatment. Finally, studies demonstrating microvascular changes in blood vessels are extremely difficult to do, but promise to yield important knowledge about cellular mechanisms and results of long-term treatment of sleep apnea on cardiovascular disease.

Postexercise hypotension in conscious SHR is attenuated by blockade of substance P receptors in NTS.

In hypertensive subjects, a single bout of dynamic exercise results in an immediate lowering of blood pressure back toward normal. This postexercise hypotension (PEH) also occurs in the spontaneously hypertensive rat (SHR). In both humans and SHRs, PEH features a decrease in sympathetic nerve discharge, suggesting the involvement of central nervous system pathways. Given that substance P is released in the nucleus tractus solitarius (NTS) by activation of baroreceptor and skeletal muscle afferent fibers during muscle contraction, we hypothesized that substance P acting at neurokinin-1 (NK-1) receptors in the NTS might contribute to PEH. We tested the hypothesis by determining, in conscious SHRs, whether NTS microinjections of the NK-1 receptor antagonist SR-140333 before exercise attenuated PEH. The antagonist, in a dose (60 pmol) that blocked substance P- and spared D,L-homocysteic acid-induced depressor responses, significantly attenuated the PEH by 37%, whereas it had no effect on blood pressure during exercise. Vehicle microinjection had no effect. The antagonist also had no effect on heart rate responses during both exercise and the PEH period. The data suggest that a substance P (NK-1) receptor mechanism in the NTS contributes to PEH.

Direct peripheral effects of ghrelin include suppression of adiponectin expression.

The stomach-derived peptide, ghrelin, has recently been discovered as an important regulator of energy homeostasis. Central nervous system pathways involving stimulation of hypothalamic neuropeptides play a prominent role in mediating ghrelin's orexigenic effects. However, potential direct peripheral effects remain poorly understood. Using a brown adipocyte model, we tested ghrelin-mediated influences on adipose tissue. Chronic ghrelin stimulation of differentiating adipocytes did not affect the pattern or extent of fat accumulation. Furthermore, insulin-induced glucose uptake as a hallmark of adipocyte function was not altered by ghrelin pre-treatment. However, acute ghrelin treatment resulted in a significant time-dependent increase in p44/42 mitogen-activated protein kinase phosphorylation. There was no stimulation of phosphatidylinositol 3-kinase, JAK/STAT, or stress kinase signaling pathways. Furthermore, ghrelin did not significantly alter gene expression of the thermogenic uncoupling protein-1. By contrast, expression of the novel adipokine adiponectin, which has been implicated in the pathogenesis of insulin resistance and obesity, was strongly impaired. This inhibition occurred acutely, and was sustained for several hours. In summary, our data provide evidence for selective effects of ghrelin on adipocyte signaling and function and thus propose a role for adipose tissue as a novel mediator of ghrelin's effects on energy balance and glucose homeostasis.

Is leptin the link between fat and bone mass?

Recently, leptin has emerged as a potential candidate responsible for protective effects of fat on bone tissue. However, it remains difficult to draw a clear picture of leptin effects on bone metabolism because published data are sometimes conflicting or apparently contradictory. Beyond differences in models or experimental procedures, it is tempting to hypothesize that leptin exerts dual effects depending on bone tissue, skeletal maturity, and/or signaling pathway. Early in life, leptin could stimulate bone growth and bone size through direct angiogenic and osteogenic effects on stromal precursor cells. Later, it may decrease bone remodeling in the mature skeleton, when trabecular bone turnover is high, by stimulating osteoprotegerin (OPG) expression. Leptin negative effects on bone formation effected through central nervous system pathway could counterbalance these peripheral and positive effects, the latter being predominant when the blood-brain barrier permeability decreases or the serum leptin level rises above a certain threshold. Thus, the sex-dependent specificity of the relationship between leptin and bone mineral density (BMD) in human studies could be, at least in part, caused by serum leptin levels that are two- to threefold higher in women than in men, independent of adiposity. Although these hypotheses remain highly speculative and require further investigations, existing studies consistently support the role of leptin as a link between fat and bone.

Increased levels of 3-hydroxykynurenine in different brain regions of rats with chronic renal insufficiency

Tryptophan (TRP) metabolism via the kynurenine pathway leads to formations of neuroactive substances like kynurenine (KYN) and 3-hydroxykynurenine (3-HK), which may be involved in the pathogenesis of several human brain diseases. 3-Hydroxykynurenine especially is known to have strong neurotoxic properties. The generation of reactive oxygen species (ROS) leads to neuronal cell death with apoptotic features. Because the chronic renal insufficiency (CRI) results in disturbances in the functioning of the central nervous system (CNS), it is conceivable that the metabolism of some kynurenines may be altered and could play an important role in uremic encephalophaty. The levels of TRP, KYN and 3-HK were measured in the plasma and in different brain regions of uremic rats. The total plasma concentration of TRP as well as in all the studied brain samples was significantly diminished during uremia. Surprisingly, the level of KYN and 3-HK were elevated both in the plasma and different brain regions of CRI animals. KYN concentrations were approximately two times higher in the cerebellum, midbrain and cortex compared to the control group. The changes of 3-HK levels were more pronounced in the striatum and medulla than in other structures. This data suggests that CRI results in deep disturbances on the kynurenine pathway in CNS, which could be responsible for neurological abnormalities seen in uremia.

Melanin-Concentrating Hormone Receptor Subtypes 1 and 2: Species-Specific Gene Expression

To assess the contribution of potential central nervous system pathways implicated in the control of appetite regulation and energy metabolism, it is essential to first identify appropriate animal models. Melanin-concentrating hormone (MCH), a conserved cyclic neuropeptide implicated in the modulation of food intake, has been shown to bind and activate two G-protein-coupled receptors, called GPR24 and MCHR2, expressed in human brain and other tissues. Here we show that several non-human species (rat, mouse, hamster, guinea pig, and rabbit) do not have functional MCHR2 receptors, or encode a nonfunctional MCHR2 pseudogene while retaining GPR24 expression. We identified three species for further evaluation that express both MCH receptor subtypes. We cloned and functionally characterized dog, ferret, and rhesus GPR24 and MCHR2 in mammalian cells and studied their brain distribution patterns by in situ hybridization. The homology, expression profile, and functional similarity of the receptors in the dog, ferret, and rhesus to that of human support the potential use of these species as preclinical animal models in the development of therapeutic agents for obesity or other MCH-mediated disorders.

Genetic labelling of specific axonal pathways in the mouse central nervous system.

We report on transgenic mouse lines in which several sensory systems in the brain are specifically visualized genetically. We employed GAP-lacZ as an axon-targeted reporter protein that was constructed by fusing the membrane-anchoring domain of the GAP-43 protein to lacZ. The reporter gene was introduced into the genome under the control of a promoter element of Brn3b transcription factor to establish transgenic mouse lines. The individual lines thus generated afforded clear images of specific axonal pathways of the visual, vomeronasal, pontocerebellar, and auditory systems. The reporter protein labelled the entire axonal process as well as the cell body of developing and mature neurons on staining with X-gal. We show that these lines facilitate the developmental and anatomical study of these neural systems. This strategy should be applicable to a variety of neural systems by using various specific promoter elements.

Development of axon pathways in the zebrafish central nervous system.

The zebrafish has a number of distinct advantages as an experimental model in developmental biology. For example, large numbers of embryos can be generated in each lay, development proceeds rapidly through a very precise temporal staging which exhibits minimal batch-to-batch variability, embryos are transparent and imaging of wholemounts negates the need for tedious histological preparation while preserving three-dimensional spatial relationships. The zebrafish nervous system is proving a convenient model for studies of axon guidance because of its small size and highly stereotypical trajectory of axons. Moreover, a simple scaffold of axon tracts and nerves is established early and provides a template for subsequent development. The ease with which this template can be visualized as well as the ability to spatially resolve individual pioneer axons enables the role of specific cell-cell and molecular interactions to be clearly deciphered. We describe here the morphology and development of the earliest axon pathways in the embryonic zebrafish central nervous system and highlight the major questions that remain to be addressed with regard to axon guidance.

PHARMACOTHERAPY FOR OROFACIAL PAIN

The sensation of pain is the means by which the body is made urgently aware of the presence of tissue damage. Pain represents a protective reflex for self-preservation. It is often pain that brings the patient to the dental office but also can be the factor that keeps the patient from seeking treatment at the appropriate time. Pain control is of great importance in dental practice. The clinician has to know the financial neuroanatomy, peripheral and central nervous system pathways, pain modulating system and various categories of pain of the head, neck and and face. Psychological and psychosocial factors also contribute to pain, whether pain arises endogenously from pathologic processes or exogenously from trauma or even dental treatment. The dentist’s task is threefold: first, to establish the correct diagnosis, second to find the cause of the pain, and third to select the treatment plan that addresses the patient’s complaint. By knowing the classification of orofacial pain, the clinician will easily make a diagnosis and determine the cause of the pain. After establishing the physical diagnosis it is easy then to determine the therapy to be made. The treatment in managing dental pain from pharmacotherapy is still effective using analgesic and local anasthetic drug.

Neurophysiology of Rett syndrome.

Neurophysiological evaluations have been widely applied in the study of Rett syndrome (RS) to provide information concerning the developmental aspects of RS; the character and extent of involvement of the central, peripheral, and autonomic nervous system pathways; and evaluation of the clinical symptomatology of RS. The electroencephalogram (EEG) is invariably abnormal and shows characteristic, though not diagnostic, changes: loss of expected developmental features; the appearance of focal, multifocal, and generalized epileptiform abnormalities; and the occurrence of rhythmic slow (theta) activity primarily in the frontal-central regions. Epileptic seizures are reported to occur frequently in RS, and partial and generalized seizures may be experienced by RS girls. However, many events presumed to be seizures have no EEG correlate during video-EEG monitoring, suggesting the possibility of a nonepileptic mechanism. Such monitoring may be necessary to determine appropriate use of antiepileptic drugs. Evoked potentials typically demonstrate intact peripheral auditory and visual pathways and suggest dysfunction of central or "higher" cortical pathways. Somatosensory-evoked potentials may be characterized by "giant" responses, suggesting cortical hyperexcitability. An increased incidence of long QT intervals during electrocardiographic recordings and diminished heart-rate variability, suggesting impairment of the autonomic nervous system, are described in RS. With the discovery of the genetic basis of RS, neurophysiological studies will provide parameters for phenotype-genotype correlations and characterization of animal models.

The transcriptional repressor ZEB regulates p73 expression at the crossroad between proliferation and differentiation.

The newly discovered p73 gene encodes a nuclear protein that has high homology with p53. Furthermore, ectopic expression of p73 in p53(+/+) and p53(-/-) cancer cells recapitulates some of the biological activities of p53 such as growth arrest, apoptosis, and differentiation. p73(-/-)-deficient mice exhibit severe defects in proper development of the central nervous system and pheromone sensory pathway. They also suffer from inflammation and infections. Here we studied the transcriptional regulation of p73 at the crossroad between proliferation and differentiation. p73 mRNA is undetectable in proliferating C2C12 cells and is expressed at very low levels in undifferentiated P19 and HL60 cells. Conversely, it is upregulated during muscle and neuronal differentiation as well as in response to tetradecanoyl phorbol acetate-induced monocytic differentiation of HL60 cells. We identified a 1-kb regulatory fragment located within the first intron of p73, which is positioned immediately upstream to the ATG codon of the second exon. This fragment exerts silencer activity on p73 as well as on heterologous promoters. The p73 intronic fragment contains six consensus binding sites for transcriptional repressor ZEB, which binds these sites in vitro and in vivo. Ectopic expression of dominant-negative ZEB (ZEB-DB) restores p73 expression in proliferating C2C12 and P19 cells. Thus, transcriptional repression of p73 expression by ZEB binding may contribute to the modulation of p73 expression during differentiation.